1. Field of the Invention
This invention relates to 4-phenylpiperidines which are useful in the treatment of disorders of the central nervous system, and to pharmaceutical compositions thereof and methods for use thereof as central nervous system disorder treatments.
A number of known antipsychotic drugs are disclosed in the art which have been shown to share a selective, high affinity for sigma receptors, which are sites where psychotomimetic opiates such as (+)-pentazocine and N-allylnormetazocine act. It has been suggested that the antipsychotic behavioral profile of these antipsychotic drugs can be attributed to their role as competitive antagonists of sigma receptor binding and that a systematic screen for drugs that block sigma receptors may provide a valuable strategy for identifying novel antipsychotic agents. Additionally, it has been shown that the relative potencies of these agents studied in vivo correspond well with their relative binding affinities obtained in vitro. See, for example, Snyder and Largent, J. Neuropsychiatry 1989, 1(1), 7-15; Largent et al., Clinical Neuropharmacology 1988, 11(2), 105-119; Taylor et al., Drug Development Research 1987, 11, 65-70; Ferris et al., Life Sciences 1986, 38(25), 2329-2337; and Su et al., Neuroscience Letters 1986, 71, 224-228.
The common property of neuroleptic drugs as sigma receptor ligands suggests that sigma interactions mediate some of the antipsychotic effects of neuroleptics. The distribution of sigma receptors in the limbic areas known to be involved in cognition and emotion supports this view.
2. Information Disclosure Statement
Piperidines having a wide variety of substituents attached to the 4-position carbon atom of the piperidine ring are known in the art. Such substituted-piperidines are also known in which one or more lower-aliphatic hydrocarbon radicals are attached to other carbon atoms of the piperidine ring. Piperidines so substituted are known having various radicals attached to the nitrogen atom of the piperidine ring, such as lower-alkyl, aralkyl, aralkenyl, aryloxyalkyl and arylmercaptoalkyl.
Miescher et al. U.S. Pat. No. 2,486,794 (issued Nov. 1, 1949) discloses compounds having the formula: ##STR2## where R" is a hydrocarbon radical, specifically methyl or ethyl and processes for the preparation thereof.
Elpern U.S. Pat. No. 2,880,211 (issued Mar. 31, 1959) discloses compounds having the formula ##STR3## where Ar is an aryl radical of the benzene or naphthylene series, Ar' is an aryl radical of the benzene series, Ac is a lower carboxylic acyl radical and X is a divalent aliphatic hydrocarbon radical of 2-6 carbon atoms. These compounds are said to be useful as analgesics.
Janssen U.S. Pat. No. 2,898,340 (issued Aug. 4, 1959) discloses compounds having the formula: ##STR4## where Ar and Ar' are aryl hydrocarbon radicals, preferably of less than nine carbon atoms, n is 2 or 3 and R is lower-alkyl, lower-alkoxy, lower-alkenyloxy, cycloalkyloxy or aryloxy. The compounds are said to be "highly active inhibitors of gastrointestinal propulsion and defecation and are therefore useful in the treatment of diarrhea".
Elpern U.S. Pat. No. 2,914,532 (issued Nov. 24, 1959) discloses lower-alkyl 4-phenyl-1-(hydrocarbonyl)-piperidine-4-carboxylates; in particular, lower-alkyl 4-phenyl-1- (3-phenylpropyl)piperidine-4-carboxylates, their acid addition salts, and the preparation of these compounds. Ethyl 1-(3-phenylpropyl)-4-phenyl-4-piperidinecarboxylate used in preparation of Example 2 is disclosed therein as Example 1. The compounds are stated to have analgesic activity.
Stern et al. U.S. Pat. Nos. 2,960,507 (issued Nov. 15, 1960) and 3,024,234 (patented Mar. 6, 1962) disclose compounds having the formula: ##STR5## where X is phenyl; Y is hydroxy or an esterified hydroxy group, (for example acetoxy or propionoxy): R is alkoxy, aryloxy, aralkoxy or cycloalkoxy or "a heterocyclic residue containing an oxygen atom" and n is an integer from 2 to 6. The compounds are said to have analgesic properties and to depress the cough-reflex center.
Elpern U.S. Pat. No. 3,043,844 (issued Jul. 10, 1962) discloses compounds having the formula: ##STR6## where Ar is a monocarbocyclic aryl radical having 6 ring carbons which are said to be useful as analgesics and antitussives.
Janssen U.S. Pat. No. 3,080,372 (issued Mar. 5, 1963) discloses compounds having the formula: ##STR7## where Ar is phenyl, halophenyl, thienyl and anisyl; Ar' is phenyl, halophenyl, alkylphenyl, anisyl or trifluoromethylphenyl; R is hydrogen, lower-alkyl, hydroxy, lower-alkyl, CHO and lower-alkanoyl. The compounds are said to have CNS depressant activity.
Janssen U.S. Pat. No. 3,141,021 (patented Jul. 14, 1964) discloses compounds having the formula: ##STR8## where Y is hydrogen, methyl,methoxy or fluorine; X is CH.sub.2 or CH.dbd.CH; n is an integer less than 4; and lower-alkyl is methyl, ethyl, propyl or butyl. The compounds are said to be useful as anticonvulsants.
Wragg et al. U.S. Pat. No. 3,209,006 (patented Sep. 28, 1965) discloses compounds having the formula: ##STR9## where X represents a straight, saturated or straight, monoethylenically unsaturated hydrocarbon chain of one of three carbon atoms; Z represents a --CH.sub.2 --, .dbd.CH--, --CO-- or --CHOH-- group, Ar represents a phenyl group substituted in the meta position by a substituent selected from chlorine, bromine and fluorine atoms and trifluoromethyl groups; R.sub.1 and R.sub.2 when taken separately represent hydrogen atoms or when taken together represent a single bond, R.sub.3 is in one of the positions meta and para and is selected from hydrogen, amino, mono-alkylamino, dialkylamino, monohydroxyalkylamino, di(hydroxyalkyl) amino, lower aliphatic acyloxyalkylamino, lower aliphatic acylamido (including lower alkane sulphonamido), N-lower alkyl aliphatic acylamido, nitro, carbamoylamino, and alkoxycarbonylamino groups; and R.sub.4 is in one of the positions meta and para and is hydrogen or an amino group. By the terms "lower", "alkyl", "alkoxy" and "hydroxyalkyl" as used throughout this specification and accompanying claims is meant alkyl, alkoxy, hydroxyalkyl and other groups containing up to 4 carbon atoms. The compounds are said to be useful as antihistaminics, hypothermic agents and local anesthetic potentiators and also to be "useful veterinary medicine".
Carabateas U.S. Pat. No. 3,217,009 (issued Nov. 9, 1965) discloses compounds having a molecular structure in which a lower-acyloxy substituent is attached to the remaining 4-position of 4-aryl-1-[.omega.-aromatic-.omega.-oxo-(lower-alkyl)]-piperidines. 4-Phenyl-1-(3-oximino-3-phenylpropyl)-4-propionoxypiperidine used as Example 7 in this specification is disclosed therein. Compounds are stated to be useful as analgesics.
Hermans et al. U.S. Pat. No. 3,539,580 (issued Nov. 10, 1970) discloses compounds having the formula: ##STR10## where R is hydrogen, lower-alkyl, halo or trifluoromethyl; R.sub.1 is di-(lower-alkyl)amino, 1-piperidinyl or 1-azepinyl; R.sub.2 is Z, Z--NH-- or Z--NH--CO--, wherein Z is phenyl or phenyl mono or disubstituted by lower-alkyl or halo; and m and n are each 2 or 3. The compounds are said to be useful as local anesthetics.
Freter et al. U.S. Pat. No. 3,627,772 (issued Dec. 14, 1971) discloses compounds having the formula: ##STR11## where R.sub.1 is hydrogen or .alpha. or .beta.-CH.sub.3 ; R.sub.2 is methyl, ethyl, n-propyl, methoxy, ethoxy or n-propoxy; R.sub.3 is methyl, hydroxy, methoxy, acetoxy, fluorine, chlorine or bromine; and X is a variety of 1-(2-propenyl) groups substituted on the 1-, 2- or 3-carbon atoms by methyl, bromine or chlorine. The compounds are said to be useful as "morphine-antagonistic analgesics".
Edenhofer et al. U.S. Pat. No. 3,674,799 (issued Jul. 4, 1972) discloses compounds having the formula: ##STR12## where R.sub.1 is hydrogen, amino, lower-alkylamino, lower-alkanoylamido, aroylamido, N-(lower-alkyl)-lower-alkanoylamido, lower-alkyl-sulfonylamido, carbamoyl or ureido; R.sub.2 is hydrogen, halogen, lower-alkyl or lower-alkoxy; R.sub.3 is halogen; R.sub.4 is hydrogen; R.sub.5 is hydrogen or hydroxy; R.sub.4 together with R.sub.5 is a carbon-carbon bond; X is --O-- or --S--; and Y is methylene, hydroxymethylene, lower-alkanoyl-oxymethylene, lower-alkylsulfonyloxymethylene, aryl-sulfonyloxymethylene or carbonyl. The compounds are said to be useful as antiphlogistic, antiallergic, antitussive or analgesic agents.
Merz et al. U.S. Pat. No. 3,708,597 (issued Jan. 2, 1973) discloses the compound ##STR13## which is said to be useful as an analgesic.
Hackmack et al. U.S. Pat. No. 4,022,786 (issued May 10, 1977) and divisional thereof Menge et al. U.S. Pat. No. 4,016,280 (patented Apr. 5, 1977) disclose 4,4-diarylpiperidines having the formula: ##STR14## where R.sub.1 is hydrogen, C.sub.1-6 alkyl, substituted or unsubstituted phenyl-lower-alkyl, hydroxy-lower-alkyl, (lower) alkyl[carbonyl or oxo](loweralkyl), lower-alkoxy-lower-alkyl, substituted or unsubstituted phenyl-lower-alkoxy-lower-alkyl, said substituents "being a halogen atom having an atomic number from 9 to 35"; R.sub.2 and R.sub.3 are independently hydrogen or C.sub.1-4 alkyl; R.sub.4 is hydrogen or R.sub.5 substituted benzoyl, where R.sub.5 has the same meanings as R.sub.2 ; and R.sub.6 is halogen or hydroxy. The compounds are said to be useful as CNS stimulants.
Japanese Patent Publication 75/024317 (published Aug. 14, 1975) discloses compounds having the formula: ##STR15## where R.sub.1 is hydrogen or lower-alkyl; R.sub.3 is hydrogen or halogen; R4 is hydrogen, halogen, lower-alkyl or trifluoromethyl; and n is 0 or 1. The compounds are said to be major tranquilizers with CNS depressant and analgisic activities.
Leander et al., Drug Dev. Res., 4(4), 421-7 (1984) discloses compounds having the formula: ##STR16## where R is methyl, phenylalkyl or allyl, which were studied for their kappa-opioid receptor antagonist activity.
The foregoing references describe compounds which may be structurally related to the compounds but are claimed to have broadly scattered and unrelated utilities. However, none of these compounds is stated to have antipsychotic properties such as those suggested for compounds of the invention.
More recently, but subsequent to our invention, Glennon et al., J. Med. Chem., 34, 3360-65 (December 1991) discloses compounds of formula: ##STR17## wherein R.sub.1 is hydrogen or hyroxy.
These compounds are reportedly sigma receptor ligands.